USPTO Patents Application 09993647

opic <9Mk^§» cipo

Office de la propriety J^JK/gmMMZ Canadian Intellectual

INTELLECTUELLE DU CANADA \ PROPERTY OFFICE

Ottawa Hull KIA 0C9

(21) (Al) 2,146,707

(22) 1995/04/10
(43) 1995/10/12

6

(51) Int. CI. C07D 207/34; C07D 307/68; C07D 333/38; C07D 401/00;

C07D 403/02; C07D 405/02; C07D 409/02; A61K 31/33

(19) (CA) APPLICATION FOR CANADIAN PATENT (12)

(54) Substituted N-Heteroaroylguanidines, a Process for Their
Preparation, Their Use as a Medicament or Diagnostic
Agent, and a Medicament Containing Them

(72) Kleemann, Heinz-Werner - Germany (Federal Republic of) ;
Lang, Hans-Jochen - Germany (Federal Republic of) ;
Schwark, Jan-Robert - Germany (Federal Republic of) ;
Weichert, Andreas - Germany (Federal Republic of) ;
Scholz, Wolfgang - Germany (Federal Republic of) ;
Albus, Udo - Germany (Federal Republic of) ;

(71) Hoechst Aktiengesellschaf t - Germany (Federal Republic
of) ;

(30) (DE) P 4412334.5 1994/04/11
(57) 17 Claims

Notice: This application is as filed and may therefore contain an

incomplete specification.

Industrie Canada Industry Canada

Canada

2146707

HOE 94/F 094

Dr . v . F .

Abstract

Substituted N-heteroaroylguanidines, a process for their
preparation, their use as a medicament or diagnostic
agent, and a medicament containing them

The invention relates to he te roar oylguani dines of the
Formula I

in which the substituents HA and R(l) to R{5) have the
meanings given in claim 1.

These compounds exhibit very good antiarrhythmic
properties, as are important for treating diseases which
occur, for example, in association with symptoms of
oxygen deficiency- As a consequence of their
pharmacological properties, the compounds are outstand-
ingly suitable for use as antiarrhythmic pharmaceuticals
possessing a cardioprotective component for the
prophylaxis and treatment of infarction and for the
treatment of angina pectoris, in connection with which
they also inhibit or strongly reduce, in a preventive
manner, the pathophysiological processes associated with
the genesis of ischemically induced damage, in particular
associated with the elicitation of ischemically induced
cardiac arrhythmias. On account of their protective
effects against pathological hypoxic and ischemic
situations, the compounds of the formula I according to
the invention can, as a consequence of inhibiting the
cellular Na + /H + exchange mechanism, be used as pharma-
ceuticals for treating all acute or chronic damage
elicited by ischemia, or diseases induced primarily or
secondarily thereby. This is the case with regard to
their use as pharmaceuticals for surgical interventions.

R<3)

R(4)

HA^R(1)

2146707

for example in organ transplantations/ where the
compounds can be used both for protecting the organs in
the donor prior to and during removal, for protecting
organs which have been removed, for example when they are
being treated with or stored in physiological bathing
fluids, and when transferring the organs into the recipi-
ent. The compounds are likewise valuable protective
pharmaceuticals to be used when carrying out angioplastic
surgical interventions, for example on the heart or on
peripheral vessels. In conformity with their ability to
protect against ischemically induced da m age, the com-
pounds are also suitable for use as pharmaceuticals for
the treatment of ischemias of the nervous system, in
particular of the CNS, in connection with which they are
suitable, for example, for the treatment of stroke or
cerebral edema. Over and above this, the compounds of the
formula I according to the invention are also suitable
for use in the treatment of forms of shock, such as, for
example, allergic, cardiogenic, hypovolemic and bacterial
shock.

2146707

Hoechst Aktiengesellschaf t HOE 94/F 094 Dr. v. F.

Description

Substituted N-heteroaroylguanidines, a process for their
preparation, their use as a medicament or diagnostic
agent, and a medicament containing them

The invention relates to heteroaroylguanidines of the
formula I

R(3) R(2)

in which:

HA is SO m , O, or NR(5),

m is zero, 1 or 2,

R(5) is hydrogen, (C^-Cg) -alkyl or -CJIj^RlSl) ,
am is zero, 1 or 2

R(81) is (C 3 -C 8 ) -cycloalkyl, or phenyl

which is not substituted or is substi-
tuted by 1-3 substituents from the group
F, CI, CF 3# methyl, methoxy or
NR(82)R(83), with R(82) and R(83) being H
or CH 3 ;

or

R{81) is (CjL-Cg) -heteroaryl

which is linked via C or N and which is
unsubstituted or is substituted by 1-3
substituents from the group F, Cl, CF 3 ,
CH 3 , methoxy, hydroxyl, amino, me thy 1-
amino, or dimethyl amino;
one of the two substituents R(l) and R{2)

is -CO-N=C (NH 2 ) 2 '
and whichever is the other is

hydrogen, F, Cl, Br, I, (C 1 -C 3 ) -alkyl , -OR(6),
C r F 2r+1 , -CO-N=C (NH 2 ) 2 or -NR(6)R(7),

R(6) and R(7) are, independently, hydrogen or
< c i" C 3> -alkyl.

2146707

- 2 -

r is 1, 2, 3 or 4,
R{3) and R(4) are, independently of each other,

hydrogen, F, CI, Br, I, -C=N, X- (CH 2 ) p - (C q -F 2q+1 ) ,
R(8)-SO bm , R(9)R(10)N-CO, R(ll)-CO-
5 or R(12)R(13)N-S0 2 -,

where the perf luoroalkyl group is straight -chain
or branched,

X is oxygen, S or NR(14),

R(14) is H or (C x -C 3 ) -alkyl ,
10 bm is zero, 1 or 2,

p is zero, 1 or 2,

q is zero, 1, 2, 3, 4, 5 or 6,

R(8), R(9), R(ll) and R(12) are, independently,
( c i" c 8> -alkyl/ (C 3 -C 6 ) -alkenyl, -C n H 2n -
15 R(15) or CF 3 ,

n is zero, 1, 2, 3 or 4,

R(15) is (C 3 -C 7 ) -cycloalkyl, or phenyl
which is not substituted or is substi-
tuted by 1-3 substituents from the group

2 0 F, CI, CF 3 , methyl, methoxy or NR(16)R(17)

with R(16) and R(17) being H or C 1 -C 4 -
alkyl,

where R(9), R(ll) and R(12) also have the meaning
of H,

25 R(10) and R(13) are, independently,

H or (C 1 -C 4 ) -alkyl,
where R(9) and R(10) and also R(12) and R(13) can
together be 4 or 5 methylene groups, of which one
CH 2 group can be replaced by oxygen, S, NH, N-CH 3

3 0 or N-benzyl,

or

R(3) and R(4) are, independently of each other,
(Ci-Cg) -alkyl or -C al H 2al R (18) ,
al iE! zero, 1 or 2,
35 R(18) ifi (C 3 -C 8 ) -cycloalkyl, or phenyl

which is not substituted or is substi-
tuted by 1-3 substituents from the group
F, CI, CF 3 , methyl, methoxy or
NR(19)R(20), with R(19) and R(20) being H

2146707

- 3 -

or CH 3 ;

or

R{3) and R(4) are, independently of each other,
(C-j^-Cg) -heteroaryl,
5 which is linked via C or N and which is unsubsti-

tuted or is substituted by 1-3 substituents from
the group F, CI, CF 3 , CH 3 , methoxy, hydroxyl ,
amino, methylamino or dimethyl ami no;

or

10 R(3) and R(4) are, independently of each other,

0

II

" Y ~\ 7-( c )h-(CH0H) I -(CH 2 ) r (CH0H) k -R(23)

^^(C) od -(CH0H) at -(CH 2 ) of -(CH0H) oc -R(24)
- Y

0

<^^^ l )^-(CH0H) oo -(CH 2 ) op -(CH0H) ak -R(25)
Y-

Y is oxygen, -S- or -NR (22 ) - ,

h, ad and ah are, independently, zero or 1,

i, j, k, ae, af, ag, ao, ap and ak are,
independently, zero, 1, 2, 3 or 4,

15 where, however, in each case,

h, i and k are not simultaneously zero,
ad, ae and ag are not simultaneously zero, and
ah, ao and ak are not simultaneously zero,
R(23), R(24), R(25) and R(22) are, independently,

20 hydrogen or (C^-C^) -alkyl,

or

R(3) and R(4) are, independently of each other,

hydrogen, F, Cl, Br, I, CN, (C^-Cg) -alkyl, (C ± -C Q ) -
perf luoroalkyl, (C 3 -C 8 ) -alkenyl or -C g H 2g R(26),
25 g is zero, 1, 2, 3 or 4,

2146707

- 4 -

R(26) is (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl
or naphthyl,

where the aromatic radicals are not sub-
stituted or are substituted by 1-3 sub-
5 stituents from the group F, CI, CF 3 ,

methyl, methoxy or NR(27)R(28), with
R(27) and R(28) being H, (C^-C^) -alkyl or
{C x -C^) -perf luoroalkyl;

or

10 R(3) and R(4) are, independently of each other,

SR(29), -OR(30), -NR(31)R(32) or -CR (3 3 ) R (34 ) R < 3 5 ) ;
R(29), R(30), R(31) and R(33) are, independently,

" C a H 2a" ^ C i" c 9^ -heteroaryl

which is unsubs tituted or is substituted
15 by 1-3 substituents from the group F, CI,

CF 3 , CH 3 , methoxy, hydroxy 1, amino,
methylamino or dimethyl amino,
a is zero, 1 or 2,
R(32), R(34) and R(35) are, independently of each
20 other, defined as R(29), or are hydrogen,

(€±-€4) -alkyl or (C^C^ -perf luoroalkyl ;

or

R(3) and R(4) are, independently of each other,

— w w —

R(96), R(97) and R{98) are, independently, (C^Cg) -

2 5 heteroaryl,

which is linked via C or N and which is
unsubstituted or is substituted by 1-3
substituents from the group F, CI, CF 3 ,
CH 3 , methoxy, hydroxyl, amino, methyl-

3 0 amino, dimethylamino or benzyl,

W is oxygen, S or NR(3 6}-,

R(36) is H or (C 1 -C 4 ) -alkyl,

or

R(3) and R(4) are, independently of each other,

2146707

- 5 -

R(37)-SO cirt or R (3 8 ) R ( 39 ) N- S0 2 - ,
cm is 1 or 2,

R(37) is (C^-Cg) -alkyl, (C^Cg) -perf luoroalkyl ,
(C 3 -C 8 ) -alkenyl or -C g H 2s -R (40 ) ,
5 s is zero, 1, 2, 3 or 4,

R(40) is (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl
cr naphthyl,

where the aromatic radicals are not sub-
stituted or are substituted by 1-3 sub-

10 stituents from the group F, CI, CF 3 ,

methyl, methoxy or NR(41)R(42), with
R{41) and R{42) being H, (C^-C^) -alkyl or
(C 1 -C±) -perf luoroalkyl;
R(38) is H, (C^Cg) -alkyl, (C^-Cg) -perf luoroalk-

15 yl,

(C 3 -C 8 ) -alkenyl or -C^^-R (43 ) ,
w is zero, 1, 2, 3 or 4,

R(43) is (C 3 -C 8 ) -cycloalkyl, phenyl,
biphenylyl or naphthyl where the

2 0 aromatic radicals are not sub-

stituted or are substituted by 1-3
substituents from the group F, CI,
CF 3 , methyl, methoxy or

NR(44)R(45), with R(44) and R(45)
25 being H, (C 1 -C 4 ) -alkyl or (C 1 -C 4 ) -

perf luoroalkyl ,
R(39) is H, (C 1 -C 4 ) -alkyl or (C x -C 4 ) -perf luoro-
alkyl ,

where R(38) and R(39) can together be 4 or 5

3 0 methylene groups, of which one CH 2 group can be

replaced by oxygen, S, NH, N-CH 3 or N-benzyl;

or

R{3) and R(4) are, independently of each other,
R(46)X(1)

35 X(l) is oxygen, S, NR(47), (D=0)A- or

NR(48)C=MN ( * } R(49) -,
M is oxygen or S,

A is oxygen or NR(50),

D is C or SO,

2146707

- 6 -

R(46) is (C^-Cg) -alkyl, (C 3 -C 8 ) -alkenyl ,

(CH 2 ) b C d F 2d+1 or -C x H 2x -R(51) ,
b is zero or 1,

d is 1, 2, 3, 4, 5, 6 or 7,

5 x is zero, 1, 2, 3 or 4,

R(51) is (C 3 -C 8 ) -cycloalkyl, phenyl,
b ipheny ly 1 , naph thy 1 ,
where the aromatic radicals are not
substituted or are substituted by
10 1-3 substituents from the group F,

CI, CF 3# methyl, methoxy or
NR(52)R(53); with R(52) and
R(53) being H, (C 1 -C 4 ) -alkyl or
(C-l-C^) -perf luoroalkyl;
15 R(47), R(48) and R(50) are, independently,

hydrogen, (C^-C^) -alkyl or {C ± -C^) -
perf luoroalkyl,

R(49) is defined as R(46), where
R(46) and R(47) and, respectively, R(46) and R(48)
2 0 can together be 4 or 5 methylene groups, of which

one CH 2 group can be replaced by oxygen, S, NH,
N-CH 3 or N-benzyl,

where A and N^* are bonded to the phenyl nucleus
of the benzoylguanidine parent substance;

25 or

R(3) and R(4) are, independently of each other,

-SR(64) , -OR (65) , -NHR(6 6) , -NR(67)R(6 8) ,

-CHR(69) R(70) ,

R(54)

-C : R(55)

OH

R(58)
_ I
-C=:C R(56), -C C-R ( 57 ) ,

R ( 59 )
C

R( 60 )

0

II

R(61 )
C

2146707

- 7 -

R(64), R(65), R(66), R(67) and R(69) are, identi-
cally or differently,

- (CH 2 ) y - (CHOH) z - (CH 2 ) aa - (CH 2 OH) t -R(71) or

- <CH 2 ) ab -0- (CH 2 -CH 2 0) ac -R(72) ,

5 R(71) and R(72) are hydrogen or methyl,

u is 1, 2, 3 or 4,
v is zero, 1 , 2 , 3 or 4 ,

y, z and aa are, identically or differently,
zero, 1, 2, 3 or 4,
10 t is 1, 2, 3 or 4,

R(68), R(70), R(54) and R(55) are, identically or
differently,

hydrogen or (C^-Cg) -alkyl, or
R(69) and R(70) and, respectively, R(54) and R(55)
15 are, together with the carbon atom carrying them, a

(C 3 -C 8 ) -cycloalkyl;
R(63) is

H, (C x -C 6 ) -alkyl, (C 3 -C 8 ) -cycloalkyl or

-C e H 2e -R(73) ,
20 e is zero, 1, 2, 3 or 4,

R(56), R(57) and R(73) are, independently,
phenyl ,

which is unsubstituted or is substituted by 1-3

substituents from the group F, CI, CF 3 , methyl,
25 methoxy or NR(74)R(75) with R(74) and R(75)

being H or (C^-C^) -alkyl,
or R(56), R(57) and R(73) are, independently,
(C-L-Cg) -heteroaryl,

which is unsubstituted or is substituted as
3 0 phenyl ;

R(58), R(59), R(60), R(61) and R(62) are hydrogen or
methyl,

or

R(3) and R(4) are, independently of each other,
35 R (76) -NH-S0 2 - ,

R(7 6) is R(77)R(78)N- <C=Y' ) -,

Y' is oxygen, S or N-R(79),

R(77) and R(78) are, identically or
differently,

2146707

- 8 -

H, (C^-Cg) -alkyl, (C 3 -C 6 ) -alkenyl,
or C f H 2f -R(80) ,
f is zero, 1, 2, 3 or 4,
R(80) is (C 5 -C 7 ) -cycloalkyl, or
5 phenyl

which is unsubstituted or is sub-
stituted by 1-3 subs tituents from
the group F, CI, CF 3 , methoxy or
(C1-C4) -alkyl, or
10 R(77) and R(78) together form 4 or 5 methylene

groups, of which one CH 2 group can be replaced by
oxygen, S, NH, N-CH 3 or N-benzyl, where
R(79) is defined as R(77) or is amidine;

or

15 R(3) and R(4) are, independently of each other,

NR(84)R(85) ,

R(84) and R(85) are, independently of each other,
H or (C^-C^) -alkyl, or, together, can be 4 or 5
methylene groups, of which one CH 2 group can be
20 replaced by oxygen, S, NH, N-CH 3 or N-benzyl,

or of which one or two CH 2 groups can be
replaced by CH-C^H^^,
and the pharmaceutically tolerated salts thereof,

where, however, compounds are excepted in which the
25 radicals R(l) to R(4) and also HA are combined in the
following manner:

R(D

R(2)

R(3)

R(4)

HA

CON=C(NH 2 )

H

H

Et

O

CON=C (NH 2 )

H

H

Me

O

CON=C(NH 2 )

H

H

H

O

Compounds of the formula I are preferred in which:

HA is SO m , O or NR(5),

m is zero, 1 or 2 ,

2146707

- 9 -

R(5) is hydrogen or methyl,
one of the two substituents R(l) and R(2) is
-CO-N=C(NH 2 ) 2 ,

and whichever is the other is hydrogen, F, CI, CH 3 , -OH
5 or -CO-N=C (NH 2 ) 2 ,

R(3) is hydrogen, F, CI, Br, I, -Cs=N, C q -F 2q+1 , R(8) -S0 2 ,
R(9)R(10)N-CO, R(ll)-CO- or R (12 ) R (13) N-S0 2 - ,

where the perf luoroalkyl group is straight -chain
or branched,
10 q is zero, 1, 2, 3, 4, 5 or 6,

R{8), R(9), R(ll) and R(12) are, independently,
(C x -C 8 ) -alkyl, (C 3 -C 4 ) -alkenyl, -C n H 2n -R(15) or
CF 3 ,

n is zero, 1, 2, 3 or 4,
15 R(15) is (C 3 -C 6 ) -cycloalkyl, or phenyl

which is not substituted or is substi-
tuted by 1-2 substituents from the
group F, CI, CF 3 , methyl, methoxy or
NR(16)R(17) # with R(16) and R(17) being H

2 0 or methyl,

where R(9), R(ll) and R(12) also have the meaning
of H,

R(10) and R(13) are, independently, H or methyl,

or

25 R(3) is (C 1 -C 8 ) -alkyl or -C al H 2al R (18) ,

al is zero, 1 or 2,

R(18) is (C 3 -C 6 ) -cycloalkyl, or phenyl

which is not substituted or is substi-
tuted by 1-2 substituents from the

3 0 group F, CI, CF 3 , methyl, methoxy or

NR(19)R(20), with R(19) and R(20) being H
or CH 3 ;

or

R(3) is quinolyl, isoquinolyl, pyrrolyl, pyridyl or
3 5 imadazolyl which are linked via C or N and

which are unsubstituted or are substituted by
1-2 substituents from the group F, CI, CF 3 ,
CH 3 , methoxy, hydroxy 1, amino, methylamino or
dime thy lamino;

2146707

- 10 -

or

R(3) is -C=CR (56) ,

R(56) is phenyl ,

which is unsubstituted or is substituted by
1-2 substituents from the group F, CI, CF 3 ,
methyl, methoxy or NR(16)R(17) # with R(16) and
R(17) being H or CH 3 ,

R(4) is

• Y_ \ V(C) h -(CH0H) !-(CH 2 ) r {CH0H) k -R(23)

or <y = J>-(C) a ,-(CH0H) fl# -(CH 2 ) of -(CH0H) og -R(24)
- Y

or <f V-(C) a(l -(CH0H) €0 -(CH 2 ) op -(CH0H). l( -R(25)

Y is oxygen, -S- or -NR (22 ) - ,
10 h, ad and ah are, independently, zero or 1,

i, k, ag, ao and ak are, independently, zero, 1, 2
or 3 ,

j , af and ap are, independently, zero or 1,

where, however, in each case,
15 h, i and k are not simultaneously zero,

ad, ae and ag are not simultaneously zero, and
ah, ao and ak are not simultaneously zero,

R(23), R(24), R(25) and R(22) are, independently,

hydrogen or methyl.

2 0 or

R(4) is hydrogen, F, CI, Br, CN, (C x -C 8 ) -alkyl, C q -F 2q+1 ,
(C 3 -C 8 ) -alkenyl or -C g H 2g R(26),

where the perf luoroalkyl group is straight- chain
or branched,
25 q is zero, 1, 2, 3 or 4,

g is zero, 1 or 2,

2146707

- 11 -

R(26) is (C 3 -C 8 ) -cycloalkyl, or phenyl

which is not substituted or is substituted by
1-2 substituents from the group F, Cl # CF 3/
methyl, methoxy or NR (27) R (28) , with R(27) and
5 R(28) being H or CH 3/

or

R(4) is SR(29) # -OR<30), -NR(31)R(32) or

-CR(33)R(34)R{35) ;

R(29), R(30), R(31) and R(33) are, independently,
10 -C a H 2a - (C 1 -C 9 ) -heteroaryl, selected from the group

consisting of pyrrolyl, imidazolyl, pyrazolyl and
pyridyl,

which is unsubstituted or is substituted

by 1-2 substituents from the group F,
15 CI, CF 3 , CH 3 , methoxy, hydroxyl , amino,

methylamino or dimethyl amino,

a is zero or 1,
R(32), R(34) and R(35) are, independently of each
other,

2 0 hydrogen or CH 3 ,

or

R(4) is

R(96) - U )>-«( 97 ) 0f (( )>—*(«)

— W

R(96), R(97) and R(98) are, independently, pyrrolyl,
imidazolyl, pyrazolyl or pyridyl,
25 which, in each case, is unsubstituted or is

substituted by 1 - 2 radicals from the group
comprising

F, CI, CF 3 , CH 3' methoxy, dimethyl amino or
benzyl ,

30 W is oxygen, S or NR(36)-,

R(36) is H or methyl,

or

R(4) is R(37)-SO cm or R <3 8 ) R ( 39 ) N-S0 2 - ,

R(37) is (C 1 -C 6 ) -alkyl, CF 3 , (C 3 -C 4 ) -alkenyl or

2146707

- 12 -

-C s H 2s -R(40) ,
s is zero or 1,

R(40) is (C 3 -C 6 ) -cycloalkyl, or phenyl

which is not substituted or is substi-
5 tuted by 1 - 2 substituents from the

group F, CI, CF 3 , methyl, methoxy or
NR(41)R(42), with R(41) and R(42) being H
or CH 3 ,

R(38) is H, (C^C^) -alkyl, CF 3 , (C 3 -C 4 ) -alkenyl or
-CwH 2w -R(43) ,
w is zero or 1

R(43) is (C 3 -C 8 ) -cycloalkyl, or phenyl

which is not substituted or is sub-
stituted by 1-2 substituents from
15 the group F, CI, CF 3 , methyl,

methoxy or NR(44)R(45), with R(44)
and R(45) being H, (C 1 -C 4 ) -alkyl or
CH 3 ,

R(39) is H or CH 3 ,
2 0 where R(38) and R{39) can together be 4 or 5

methylene groups, of which one CH 2 group can be
replaced by oxygen, S, NH, N-CH 3 or N-benzyl;

or

R(4) is R(46)X(1)
25 X(l) is oxygen, S, NR(47), (C=0)A- or

NR(4 8) C=MN (M R(49) - ,
M is oxygen,
A is oxygen or NR(50),
R(46) is (C x -C 6 ) -alkyl, (C 3 -C 4 ) -alkenyl,

30 (CH 2 ) b C d F 2d+1 or -C x H 2x -R (51) ,

b is zero or 1,
d is 1, 2, 3, 4, 5, 6 or 7,
x is zero or 1,

R(51) is (C 3 -C 8 ) -cycloalkyl, or phenyl
35 which is not substituted or is sub-

stituted by 1-2 substituents from
the group F, CI, CF 3 , methyl,
methoxy or NR(52)R(53); with R(52)
and R(53) being H or CH 3 ,

2146707

- 13 -

10

or

R(47) , R(48) and R{50)

are hydrogen or (C 1 -C 4 ) -alkyl,
R(49) is defined as R(46), where

R(46) and R(47) and, respectively, R(46) and
R(48) can together be 4 or 5 methylene groups;
of which one CH 2 group can be replaced by
oxygen, S, NH, N-CH 3 or N-benzyl,
where A and N ( ** are bonded to the phenyl

nucleus of
substance ;

the benzoylguanidine parent

R(4) is -SR(64), -OR(65),
-CHR(69)R(70) ,

-NHR(6 6) , -NR(67)R(68) ,

R(54)

- R ( 55 )
OH

R ( 58 )

-CECR (56), -C C-R ( 5 7 ) or

R ( 59 )

-C

I

R ( 6 0 )

0

II

R(61 )

_ R(62)_

-R ( 6 3 )

R(64), R(65), R(66), R(67) and R(69) are,
15 identically or differently,

- (CH 2 ) y - (CHOH) z - (CH 2 ) aa - (CH 2 OH) t -R(71) or

- (CH 2 ) ab -0-(CH 2 -CH 2 0) ac -R(72) ,

R(71) and R(72) are hydrogen or methyl,
u is 1 or 2,
20 v is zero, 1 or 2,

y, z and aa are, identically or differently,

zero, 1 or 2 ,
t is 1, 2 or 3,
R(68), R(70), R(54) and R(55) are, identically or
25 differently,

hydrogen or CH 3 ,

or

R(69) and R(70) and, respectively, R(54) and R(55)
are, together with the carbon atom carrying them, a

2146707

- 14 -

(C 3 -C 6 ) -cycloalkyl;
R(63) is

H, (C^-C^) -alkyl, (C 3 -C 6 ) -cycloalkyl or

-C e H 2e -R(73) ,
5 e is zero, 1 or 2,

R(56), R(57) and R(73) are, independently,
phenyl

which is unsubstituted or is substituted
by 1-2 substituents from the group F,
10 CI, CF 3 , methyl, methoxy or NR(74)R(75),

with R(74) and R(75) being H or CH 3 ,

or

R(56), R(57) and R{73) are, independently,

(C 1 -C 5 ) -heteroaryl, selected from the group consist-
15 ing of pyrrolyl, imidazolyl, pyrazolyl and pyridyl,

which is unsubstituted or is substituted
as phenyl;
R(58), R(59), R(60), R(61) and R(62)
are hydrogen or methyl,

20 or

R(4) is R(76) -NH-S0 2 -,

R(76) is R(77)R(78)N- (C=Y' ) -,
Y' is oxygen, S or N-R(79),

R(77) and R(78) are, identically or
25 differently,

H, (C x -C^) -alkyl, (C 3 -C 4 ) -alkenyl or
-C f H 2f -R(80) ,
f is zero or 1,
R(80) is

30 (C 5 -C 7 ) -cycloalkyl, or phenyl

which is unsubstituted or is
substituted by 1-2 substi-
tuents from the group F, CI,
CF 3 , methoxy or CH 3 , or
35 R(77) and R(78) together f orm 4 or o

methylene groups, of which one CH 2 group
can be replaced by oxygen, S, NH, N-CH 3 or
N-benzyl, where
R(79) is defined as R(77),

2146707

— J. 5 —

or

R(4) is NR(84)R(85) ,

R(84) and R(85) are, independently of each other,
H or {C x -C^) -alkyl , or together form 4 or 5
5 methylene groups, of which one CH 2 group can be

replaced by oxygen, S, NH, N-CH 3 or N-benzyl,
or of which one or two CH 2 groups can be
replaced by CH-CH 3 .

Compounds of the formula I are particularly preferred in
10 which:

RCD is

-CO-N=C (NH 2 ) 2

HA is

S, O, NH or NCH 3 ,
15 and the radicals R(2) to R(4) are combined as follows:

2146707

- 16 -

R(2)

R(3)

R(4)

H

n-BuNH-

CI

H

H 2 NS0 2 -

H

MeS0 2

H

O'-

Me

H

er-

<o>-°-

H

\ /

Me

H

CI

H

o-

MeS0 2 -

2146707

- 17 -

1 H

MeSOo

NH 2

H

MeS0 2 -

Cr" H -

H

MeS0 2 -

\ ■ f

H

MeS0 2 -

C 1

H

MeSOo-

H

MeS0 2 -

H

MeSOo-

N H - 1

H

Cl-

o-

H

MeS0 2 .

(CH 3 ) r CHCH 2 -0-

H

MeS0 2 .

H

MeS0 2 .

/Me

H

MeS0 2

M e

2146707

H

C I

H

C I

C I

H

H

\/ N "

C I

a

H

OMt

H

£5

H

MeS0 2 -

C I

C I

H

MeSOo-

c I

C I

Me

H

TT

Me
MeSO

CF.

H

i-Pr
TT

2116707

- 19 -

H

Cl

H

MeS0 2 -

MeNH-

H

MeS0 2 -

Et 2 N-

H

t-Bu

Oh

H

MeS0 2 -

C K

H

MeSO r

M e 0

H

MeS0 2 -

H

MeSU 2 -

C 1

H

MeS0 2 -

\ /

H

MeSCU-

2-Naphthyl

H

MeS0 2 -

H

o-

Me

M

o-

Me

<o>—

H

CI

Et 2 N-

H

Me 2 N-

M

- ™ - 2146707

H

MeS0 2 -

_ r 1
0

H

Br

NH 2

H

CI

H

H

MeS0 2 -

H

MeS0 2 -

F -<0- 0 -

/

C 1

H

CF 3

CF 3

H

Me

Me

H

1

CF 3

H

Me

H

H

H

t-Bu

H

MeS0 2 -

H

Me

CI

H

Br

Me

H

CI

MeO-

H

MeCO-

Cr

H

Br

Br

H

MeS0 2 -

^-^^T H j - C H 2 -

H

MeS0 2 -

a,.,.

NH 2

Br

Me

2146707

- 21 -

H

Me 2 N-

t-Bu

H

MeS0 2 -

H °-<0>~ 0 "

H

\ — /

H

H

MeO-

H

Me

Br

H

CI

fi

H

t-Bu

H

NH 2

CI

H

H

\-f

Me 2 N

H

Me 2 N

CI

H

MeS0 2 -

7-lsoquinolinoxy

H

MeSO z -

6-quinolinoxy

H

MeS0 2 -

H

MeS0 2 -

0

H

MeS0 2 -

H

MeS0 2 -

Cr

H

Me 2 N-

H

Me 2 N-

H

Me

Me 2 N-

2146707

- 22 -

H

<y n -

\— /

H

Ma

1 VIC

Cr

H

CI

i-Pr

H

i-Pr

H

MeS0 2 -

5-quinolinoxy

H

Cr

CF 3

H

i-Pr

MeS0 2 -

H

i-Pr

CF 3

H

H

i-Pr

NH 2

Br

Br

H

MeSO,-

OH

H

\=J

MeS0 2 -

H

MeS0 2 -

1

Bn

H

Cl

O^D— MM ^HH-

H

MeoN

i-Pr

H

MeHN-

i-Pr

H

Cl

CI

H

Me

H 2 N-

H

CI

H 2 N

2146707

- 23 -

H

MeS0 2 -

H

H

MeS0 2 -

M e

/

< -

M e

H

Me 2 N-

i-Pr

CF 3

H

CF 3

H

Br

Me

H

Me

CI

H

Me 2 N

Me

H

CF 3

MeHN-

H

CH3CO-

H

MeS0 2 -

H

CF3-O-

H

H

Me

Me 2 N

H

CI

Me 2 N-

H

MeS0 2 -

H

CH3CO-

i-Pr

H

Br

BnO-

H

CF 3

Br

H

i-Pr

MeO-

n

1VIU0VJ2

H

MeS0 2 -

2146707

- 24 -

H

MeO-

t-Bu

H
CF
~H
TT

H

Br

TT
"cT;

Th

i-Pr

1-lmidazolyl

H

MeCO-

t-Butylmethyl

H

Br

H

Br

MeO-

H

CF.

PhO-
Cyclopentyl

H

CF.

H

MeS0 2 -

Cyclobutyl

H

Me

CF

H

MeSO a -

H

OH

t-Butyl

H

CI

OMe

H

CF.

i-Pr

CF.

H

H

CF.

H

t-Butyl

OMe

H

MeCO-

H

MeCO-

H

t-Butyl

i-Butyl

H

CF 3 CF 2 -

i- Propyl

2146707

- 25 -

H

CF 3 -S0 2 -

CI

CF 3

H

CI

H

CF 3

it

n

II

n

"61 TiuorO"i-prupyi

H

1 1
n

n

H

MeS0 2

H

H

Perfluoro-n-propyl

H

CF 3

H

CF 3

H

CF 3

H

F

CF 3

T ii

NH

H

t-Butyl

i-Propyl

H

t-Butyl

n-Butyl

H

i-Propyl

F

H

i-Butyl

F

H

CI

1-lmidazolyl

H

H

CF 3 -CF 2 -

H

H

CF 3

2146707

- 26 -

H

H

F S C v

J*

H

MeS0 2

H

CF 3 S0 2

i-propyl

(C-L-Cg) -Heteroaryl is understood to mean, in particular,
radicals which are derived from phenyl or naphthyl and in
which one or more CH groups is/are replaced by N f and/or
in which at least two adjacent CH groups are replaced
5 (with the formation of a f ive-membered aromatic ring) by
S, NH or O. In addition, one or both atoms of the conden-
sation site of bicyclic radicals may also be N atoms (as
in indolizinyl) .

Heteroaryl is, in particular, furanyl, thienyl, pyrrolyl,
10 imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl , pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, indolyl, indazolyl, quinolyl,
isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and
cinnolinyl .

15 If one of the substituents R(l) to R(5) contains one or
more centers of asymmetry, these latter can be either in
the S or R configuration. The compounds may be present as
optical isomers, as diastereomers, as racemates, or as
mixtures thereof .

2 0 The designated alkyl radicals may be either straight -
chain or branched.

The invention furthermore relates to a process for

2146707

- 27 -

preparing compounds I, wherein compounds
of the formula II

0

in which L is a leaving group which can readily be
substituted nucleophilically , are reacted with guanidine.

5 The activated acid derivatives of the formula II in which
L is an alkoxy, preferably a methoxy, group, a phenoxy
group, a phenyl thio, methylthio or 2-pyridylthio group,
or a nitrogen heterocycle, preferably 1-imidazolyl, are
advantageously obtained, in a manner known per se, from

10 the underlying carbonyl chlorides (formula II, L = CI) ,
which for their part, can be prepared, once again in a
manner known per se, from the underlying carboxylic acids
(formula II, L = OH), for example using thionyl chloride.
In addition to the carbonyl chlorides of the formula II

15 (L = CI) , other activated acid derivatives of the formula
II can also be prepared, in a manner known per se,
directly from the underlying heteroarylcarboxylic acid
derivatives (formula II, L ■ OH) as can, for example, the
methyl esters of the formula II with L - OCH 3 by treat -

2 0 ment with gaseous HC1 in methanol, the imidazolides of
the formula II by treatment with carbonyldiimidazole
[L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1,
351-367 (1962)], the mixed anhydrides II with Cl-COOC 2 H 5
or tosyl chloride in the presence of triethylamine in an

25 inert solvent, in addition to which there is also the
activation of heteiroarylcarboxylic acids with dicyclo-
hexylcarbodiimide (DCC) or with O- [ (cyano (ethoxy-
carbonyl ) methylene) amino] -1,1,3,3- tetrame thyluronium
tetraf luoroborate ("TOTU" ) [Proceedings of the 21st

30 European Peptide Symposium, Peptides 1990, Editors

2146707

- 28 -

E. Giralt and D. Andreu, Escom, Leiden, 1991] . A series
of suitable methods for preparing activated carboxylic
acid derivatives of the formula II is given, with
citation of the source literature, on p. 350 in J. March,
5 Advanced Organic Chemistry, Third Edition (John Wiley &
Sons, 1985) .

An activated carboxylic acid derivative of the formula I
is reacted with guanidine, in a manner known per se, in
a protic or aprotic polar, but nevertheless inert,

10 organic solvent. In this context, methanol, isopropanol
or THF, at a temperature of from 20°C up to the boiling
temperature of these solvents, have proved of value when
reacting the methyl heteroarylcarboxylates (II, L = OMe)
with guanidine. Most of the reactions of compounds II

15 with salt -free guanidine were advantageously carried out
in inert solvents such as THF, dime thoxy ethane, dioxane
or isopropanol. However, water can also be used as the
solvent .

When L is CI, the reaction is advantageously carried out

2 0 with the addition of an acid- capturing agent, for example

in the form of excess guanidine, for binding the hydro -
halic acid.

Some of the underlying heteroaryl carboxylic acid deriva-
tives of the formula II are known and described in the
25 literature. The unknown compounds of the formula II may
be prepared by methods which are known from the litera-
ture, by, for example, converting 5-halo-4-chlorosul-
fonylbenzoic acids, with ammonia or amines, into 4-
aminosulf onyl- 5-halo-heteroarylcarboxylic acids, or, with

3 0 a weak reducing agent, such as sodium bisulfite, and

subsequent alkylation, into 4-alkylsulfonyl-5-halo-
heteroarylcarboxylic acids, and transforming them, by one
of the above-described process variants, into compounds
I according to the invention.

3 5 The introduction of substituted sulfur nucleophiles,

2146707

- 29 -

oxygen nucleophiles or nitrogen nucleophiles is achieved
using methods, which are known from the literature, for
nucleophilic substitution in an aromatic compound. In
this substitution, halides and trif luorome thane sulf onates
5 have proved to be of value as leaving groups. The reac-
tion is advantageously carried out in a dipolar aprotic
solvent, such as, for example, DMF or TMU, at a tempera-
ture of between 0°C and the boiling point of the solvent,
preferably between 80 °C and the boiling point of the
10 solvent. An alkali metal salt or alkaline earth metal
salt having an anion of high basicity and low nucleo-
philicity, such as, for example, K 2 C0 3 , is advantageously
used as acid- capturing agent.

The introduction of the alkyl or aryl substituents is
15 achieved by the methods, which are known from the litera-
ture, of palladium-mediated cross -coupling of aryl
halides with, for example, organozinc compounds,
organos tannanes , organoboronic acids or organoboranes .

In general, heteroaroylguanidines I are weak bases and
2 0 can bind acid with the formation of salts. Suitable acid
addition salts are the salts of all pharmacologically
tolerated acids, for example halides, in particular
hydrochlorides, lactates, sulfates, citrates, tartrates,
acetates, phosphates, methylsulf onates and p- toluenesul -

2 5 f onates .

It was surprising that, while the compounds according to
the invention do not exhibit any undesirable and dis-
advantageous salidiuretic properties, they do exhibit
very good antiarrhythmic properties, as are important for

3 0 treating diseases which occur, for example, in asso-

ciation with symptoms of oxygen deficiency. As a con-
sequence of their pharmacological properties, the com-
pounds are outstandingly suitable for use as anti-
arrhythmic pharmaceuticals possessing a cardioprotective
3 5 component for the prophylaxis and treatment of infarction
and for the treatment of angina pectoris, in connection

2146707

- 30 -

with which they also inhibit or strongly reduce, in a
preventive manner, the pathophysiological processes
associated with the genesis of ischemically induced
damage, in particular associated with the elicitation of
5 ischemically induced cardiac arrhythmias* On account of
their protective effects against pathological hypoxic and
ischemic situations, the compounds of the formula I
according to the invention can, as a consequence of
inhibiting the cellular Na + /H + exchange mechanism, be

10 used as pharmaceuticals for treating all acute or chronic
damage elicited by ischemia, or diseases induced
primarily or secondarily thereby. This is the case with
regard to their use as pharmaceuticals for surgical
interventions, for example in organ transplantations,

15 where the compounds can be used both for protecting
the organs in the donor prior to and during removal,
for protecting organs which have been removed, for
example when they are being treated with or stored in
physiological bathing fluids, and when transferring the

2 0 organs into the recipient* The compounds are likewise
valuable protective pharmaceuticals to be used when
carrying out angioplastic surgical interventions, for
example on the heart or on peripheral vessels. In con-
formity with their ability to protect against ischemi-

2 5 cally induced damage, the compounds are also suitable for

use as pharmaceuticals for the treatment of ischemias of
the nervous system, in particular of the CNS, in
connection with which they are suitable, for example, for
the treatment of stroke or cerebral edema. Over and above

3 0 this, the compounds of the formula I according to the

invention are also suitable for use in the treatment of
forms of shock, such as, for example, allergic, cardio-
genic, hypovolemic and bacterial shock.

In addition to this, the compounds of the formula I
3 5 according to the invention are notable for their strong
inhibitory effect on the proliferation of cells, for
example the proliferation of fibroblast cells and the
proliferation of the smooth muscle cells of the blood

2146707

- 31 -

vessels. For this reason/ the compounds of the formula I
are valuable therapeutic agents for use in diseases in
which cell proliferation represents a primary or secon-
dary cause and may, therefore, be used as antiathero-
5 sclerotic agents, and as agents against diabetic late
complications, cancerous diseases, fibrotic diseases such
as pulmonary fibrosis, hepatic fibrosis or renal fibro-
sis, and against organ hypertrophies or hyperplasias, in
particular hyperplasia or hypertrophy of the prostate.

10 The compounds according to the invention are efficient
inhibitors of the cellular sodium/proton antiporter
(Na + /H + exchanger) , which, in numerous diseases (essen-
tial hypertension, atherosclerosis, diabetes, etc.), is
also elevated in those cells which are readily accessible

15 to measurement, such as, for example, erythrocytes,
thrombocytes or leucocytes • The compounds according to
the invention therefore represent outstanding and simple
scientific tools, for example in their use as diagnostic
agents for defining and differentiating particular forms

2 0 of hypertension and also of atherosclerosis, diabetes,
proliferative diseases, etc. In addition to this, the
compounds of the formula I can suitably be used in
preventive therapy for preventing the genesis of high
blood pressure, for example of essential hypertension.

2 5 The compounds according to the invention exhibit a

solubility in water which is significantly superior to
that of the known compounds. For this reason, their
suitability for i.v. administration is considerably
greater.

3 0 In this context, pharmaceuticals which contain a compound

I may be administered orally, parenterally , intravenously
or rectally, or by inhalation, the preferred route of
administration depending on the given features of the
disease. In this context, the compounds I may be used
35 either alone or together with pharmaceutical auxiliary
substances, both in veterinary and in human medicine.

2146707

- 32 -

Owing to his specialist knowledge, the person skilled in
the art is familiar with those auxiliary substances which
are suitable for the desired pharmaceutical formulation.
Antioxidants, dispersants, emulsifiers, defoamers, taste
5 corrigents, preservatives, solubilizers or dyes, for
example, can be used in addition to solvents, gel for-
mers, suppository bases, tablet auxiliaries and other
active compound excipients.

For a form for oral use, the active compounds are mixed
10 with the additives, such as carrier substances, stabil-
izers or inert diluents, which are suitable for the
purpose, and brought by the customary methods into the
forms, such as tablets, coated tablets, hard gelatin
capsules, or aqueous, alcoholic or oily solutions, which
15 are suitable for administration. Gum arabic, magnesium
oxide, magnesium carbonate, potassium phosphate, lactose,
glucose or starch, in particular corn starch, can, for
example, be used as inert excipients. In this context,
the preparation can be effected either as a dry granulate

2 0 or as a wet granulate. Vegetable or animal oils, for

example, such as sunflower oil or cod-liver oil, are
suitable for use as oily excipients or as solvents.

For subcutaneous or intravenous administration, the
active compounds are brought into solution, suspension or
25 emulsion, if desired using the substances, such as
solubilizers, emulsifiers or other auxiliary substances,
which are customary for the purpose. Examples of suitable
solvents are: water, physiological sodium chloride
solution or alcohols, for example ethanol, propanol or

3 0 glycerol, as well as sugar solutions, such as glucose or

mannitol solutions, or else a mixture of the different
solvents mentioned.

Solutions, suspensions or emulsions of the active com-
pound of the formula I in a pharmaceutically harmless
35 solvent, such as, in particular, ethanol or water, or in
a mixture of such solvents, represent examples of

2146707

- 33 -

suitable pharmaceutical formulations for administration
in the form of aerosols or sprays. As required, the
formulation can also contain additional pharmaceutical
auxiliary substances such as surfactants, emulsifiers and
5 stabilizers, as well as a propellent gas. Such a prepa-
ration customarily contains the active compound in a
concentration of from about 0.1 to 10, in particular of
from about 0.3 to 3, % by weight.

The dosage of the active compound of the formula I to be
10 administered, and the frequency of administration, depend
on the strength and duration of the effect of the com-
pounds used; additionally also on the nature and severity
of the disease to be treated and on the sex, age, weight
and individual responsiveness of the mammalian subject to
15 be treated.

On average, the daily dose of a compound of the formula
I is, for a patient of approximately 7 5 kg in weight, at
least 0.001 mg, preferably 0.01 mg to 10 mg, preferably
1 mg. In acute manifestations of the disease, for example

2 0 immediately after suffering a cardiac infarction, even
greater and, in particular, more frequent dosages may
also be necessary, for example up to 4 individual doses
per day. In the case of i.v. use in particular, for
example in an infarction patient in intensive care, up to

2 5 10 0 mg per day may be necessary.

The novel compounds of the formula I which are listed
below, and their physiologically tolerated salts, can be
prepared in analogy with the instructions given in the
exemplary embodiments :

30 List of abbreviations:

MeOH methanol

DMF N, N-dimethylf ormamide

TMU N,N,N' ,N' - tetramethylurea

NBS N-bromosuccinimide

2148707

- 34 -

TP T

-L

Hpcnrnt - 1 nn rhemical ionisation

S.\ C £9 \J JL k> l»* .L. vXJL XX CUi J* c& >JL> WX1 ^ 0 W aht X 4

PT

T*0/-lTn f" ^TTIT*! ^ T* ^ T 1 T* P>
X. U vJxll L* T 1 1 1 } ■> CX. CL u> m. C

c

o

JJxxr

MTB

meunyj. cert-JDUtyx ecner

mp

Kieicing point

XX ilep Uctllc?

i n

FiMTP

■? tti o t" nwo ^Vi an o

TP A T3

aLQm JJ CJXILXJ<x X. HILL ell L.

L - tl 2 U - L 2

/-I -J /-i Vi "} /~\ t* i^i tti arVisr O
tiiLiiiui 'Jill 1 ? l» xxcixi

f- pf rahvdrof uran

eq

ami *i Tra 1 pn t~
cu ux v ax exx i—

Id

^-s T m X» <u « « 4— ^> « «m m ^ y J ^| m 3 ^™ m

ei6C uxOS LdCIC SpXTay lUIllZaulUU

Me

methyl

Et

ethyl

Bn

benzyl

CNS

central nervous system

20

brine

saturated aqueous solution of NaCl

Experimental Section
Example 1

5 -Hep taf luoroi sopropyl - 1 -me thy lpyrrole - 2 - carboguanidide

a) Methyl 5 -heptaf luoroi sopropyl -1-methylpyr role -2 -car -
25 boxylate

1.1 g of methyl l-methylpyrrole-2 -carboxylate, 1.7 ml of
perf luorooisopropyl iodide and 1.3 g of FeS0 4 x 7 H 2 0 are
initially introduced in 80 ml of DMSO, and 4 . 1 ml of
H 2 0 2 (35%) are slowly added dropwise at RT. The mixture is

3 0 stirred at RT for 1.5 h and then extracted 3 x with
200 ml of MTB on each occasion, and the organic phase is
additionally washed 1 x with 100 ml of water and 2 x with
100 ml of brine. Drying takes place over Na 2 S0 4 and the
solvent is removed in vacuo. Chromatography using EA/HEP

35 1/4 gives 310 mg of a colorless oil.

R f (EA/HEP 1/4) = 0.62 MS (DCI) : 308 (M + H) +

2146707

- 35 -

b) 5 -Heptaf luoroisopropyl - 1 -methylpyrrole- 2 -carbo-
guanidide

310 mg of methyl 5-heptaf luoroisopropyl -1 -methylpyrrole -
2 -carboxylate and 295 mg of guanidine are boiled under
5 reflux, for 4 h, in 5 ml of anhydrous isopropanol. The
solvent is removed in vacuo and the residue is chromato-
graphed using EA. 123 mg of a colorless oil are obtained.
R f (EA) = 0.26 MS (ES) : 335 (M + H) +

Conversion into the hydrochloride yields white crystals,
10 mp 165°C

The title compounds in Examples 2-5 are synthesized in
analogy with Example 1:

Example 2

5 -Heptaf luoro-n -propyl- 1 -methylpyrrole - 2 -carboguanidide
15 R f (EA) = 0.20 MS (ES) : 335 (M + H) +

mp (hydrochloride) : 207 °C

Example 3

5 -Pentaf luoroethyl-1 -methylpyrrole -2 -carboguanidide
R f (EA) =0.16 MS (DCI) : 285 (M + H) +

2 0 mp (hydrochloride) : 210 °C

Example 4

5 - Tr if luoromethyl- 1 -methylpyrrole- 2 -carboguanidide
R f (EA) = 0.16 MS (DCI): 235 (M + H) +

mp (hydrochloride) : 23 0 °C

2 5 Example 5

1 -Me thylpyrrole - 2 - carboguanidide

R f (EA/MeOH 10:1) = 0.13 MS(ES): 167 (M + H) +

mp (hydrochloride) : 255 °C

Example 6

3 0 5 - Isopropyl - 4 -methyl sul f onyl thiophene - 2 - carboguanidide

a) 5 -bromo thiophene - 2 - carboxylic acid

10 g of thiophene- 2 -carboxylic acid are dissolved in

2146707

- 36 -

100 ml of acetic acid and 100 ml of water, and a solution
of 4 ml of bromine in 50 ml of acetic acid and 50 ml of
water is added dropwise, at 0°C, over a period of one
hour. The mixture is subsequently stirred at 0°C for 1 h
5 and the product is then filtered off with suction and
recrystallized from water. 4.8 g of colorless crystals
are obtained, mp 140°C

R f (MTB 2% HOAc) =0,54 MS (DCI) : 207 (M + H) +

b ) 5 - Br omo - 4 - chlorosul f ony 1 thiophene - 2 - carboxy 1 ic acid
10 37 g of 5-bromothiophene-2-carboxylic acid are dissolved,

at RT, in 133 ml of chlorosul fonic acid, and this mixture
is stirred at 100 °C for 45 min. The mixture is
subsequently poured onto 1 kg of ice and the product is
filtered off with suction. 53 g of a colorless solid are
15 obtained, mp 96°C

R f (MTB 2% HOAc) =0.3 MS (DCI) : 305 (M + H) +

c) 5-Bromo-4-hydroxysulf inyl thiophene -2 -carboxylic acid
27.5 g of sodium sulfite are dissolved in 300 ml of
water, and a total of 35 g of 5-bromo-4-chlorosulf onyl-

2 0 thiophene- 2 -carboxylic acid is added, in portions, at
7 0°C, with a pH of 9 - 11 being maintained using 10 N
NaOH. The mixture is subsequently stirred at 70°C for 2 h
and then adjusted to pH = 1 with HC1, after which the
product is filtered off with suction. 41 g of colorless

25 crystals are obtained.

mp 195 °C (decomposition)

d) 5-Bromo-4-hydroxysulf inylthiophene-2 -carboxylic acid,
disodium salt

41 g of 5 - br omo - 4 - hy dr oxy sul f inyl t hi ophene - 2 - c arboxy 1 i c
30 acid are suspended in 150 ml of water, and 90 ml of 2 N
NaOH are added (pH = 10) . The water is removed in vacuo,
the residue is stirred up in 1 1 of acetone, and the
product is filtered off with suction. 46 g are obtained
of a colorless, amorphous solid, which is immediately
35 subjected to further reaction.

2146707

- 37 -

e) Methyl 5 -bromo-4 -methylsulf onylthiophene- 2 -carboxylate
46 g of the title compound 6 d) are suspended in 15 0 ml
of DMF , and 3 2 ml of methyl iodide are added. The mixture
is stirred at 50 °C for 5 h and then poured onto 1 1 of

5 water; the product is filtered off with suction. 35 g of
a colorless solid are obtained, mp 135°C
R f (DIP) = 0.20 MS(DCI): 299 (M + H) +

f ) Methyl 5 - isopropyl - 4 -methylsulf onylthiophene- 2 - car-
boxylate

10 3 0 ml of a 2 M solution of isopropylmagnesium chloride in
THF are added to 140 ml of a 0.5 M solution of zinc
chloride in THF. The mixture is stirred at 50 °C for 5 h
and the resulting isopropylzinc derivative undergoes
further use as solution A. 6 g of methyl 5 -bromo - 4 -

15 methylsulfonylthiophene-2 -carboxylate, 0.6 g of [1,1'-
bis (diphenylphosphino) ferrocene] Pd(II) Cl 2 x CH 2 C1 2 and
180 mg of Cul are stirred, at RT for 10 min, in 100 ml of
anhydrous THF, and solution A is subsequently added
dropwise. The mixture is subsequently stirred at RT for

20 18 h, and the solvent is then removed in vacuo. The
residue is suspended in 2 00 ml of a saturated aqueous
solution of NaHS0 4 , and this suspension is extracted 3 x
with 2 00 ml of EA on each occasion. Drying takes place
over Na 2 S0 4 , the solvent is removed in vacuo, and the

2 5 residue is chromatographed using once in each case, DIP

and EA/HEP 1:3. 1.7 g of a colorless oil are obtained.
R f (DIP) = 0.29 R f (EA/HEP 1:3) = 0.32

MS(DCI) : 263 CM + H) +

g) 5 - Isopropyl - 4 -methylsulf onylthiophene - 2 - carboguanidide
30 700 mg of methyl 5-isopropyl-4-methylsulf onylthiophene -2 -

carboxylate and 7 90 mg of guanidine are dissolved in 5 ml
of anhydrous isopropanol, and this mixture is boiled
under reflux for 1 h. The solvent is removed in vacuo and
80 ml of water are added; the mixture is adjusted to

3 5 pH = 2 with aqueous HCl, and the product is filtered off.

The precipitate is dissolved in 50 ml of a saturated
aqueous solution of Na 2 C0 3 , and this solution is

. 3 8 - 2146707

extracted 3 x with 50 ml of EA on each occasion. The
organic phase is dried over Na 2 S0 4 , and the solvent is
removed in vacuo. 850 mg of an amorphous solid are
obtained .

R f (MeOH/EA 1:10) = 0.41 MS(ES): 290 (M + H) +

mp (hydrochloride) : 2 67 °C

mp (methanesulf onate) : 12 8 °C

The title compounds of Examples 7, 8 and 10 were
synthesized in analogy with Example 6 g) :

Example 7

5 -Methyl thiophene-2 -carboguanidide

mp (hydrochloride) : 236°C MS(DCI) : 184 (M + H) +

Example 8

4 , 5 -Dibromothiophene- 2 -carboguanidide

mp (hydrochloride) : 268°C MS(DCI) : 326 (M + H) +

Example 9

4- Isopropyl- 5 -methyl sulfonyl thiophene-2 -carboguanidide

a) 4 - Bromo - 5 -methyl thiothiophene - 2 - carboxylic acid

25 g of 4, 5-dibromothiophenecarboxylic acid, 12.2 g of
NaSCH 3 and 60 g of K 2 C0 3 are stirred, at 120 °C for 5 h, in
1 1 of DMF. This mixture is then poured onto 3 1 of
water, and the pH of the resulting mixture is adjusted to
1 with HC1; the product is filtered off with suction and
used for further reaction without purification.
Yield: 14 g of amorphous powder.
R f (DIP 2% HOAc) = 0.4 6

b ) 4 - Bromo - 5 - me thy 1 sul f ony 1 thi ophene - 2 - carboxy 1 i c ac id
14 g of the methylthio compound 9 a) are dissolved in
50 0 ml of CH 2 C1 2 , and 41 g of m-chloroperbenzoic acid are
then added in portions. The mixture is stirred at RT for
1.5 h, and the solvent is then removed in vacuo and the
product is esterified without purification.

R f (DIP 2% HOAc) = 0.10

2146707

- 39 -

c ) Methyl 4 -bromo - 5 -me thy 1 sul f onyl thiophene - 2 - carboxy la t e
50 ml of SOCl 2 are added to the whole of the crude
product from Example 9 b) in 200 ml of Me OH, and this
mixture is boiled under reflux for 5 h. Excess S0C1 2 and

5 the solvent are removed in vacuo and the residue is
chroma tographed using DIP. 11 g of a colorless oil are
obtained .

R f (DIP) = 0.28 MS(DCI) : 299 (M + H) +

d) Methyl 4 - is ©propyl - 5 -me thy 1 sul f onyl thiophene- 2 - car-
lo boxylate

3 0 ml of a 2 M solution of isopropylmagnesium chloride in
diethyl ether are added dropwise to a 1 M solution of
ZnCl 2 in diethyl ether, and this mixture is boiled under
reflux for 6 h. (Solution A)

15 6 g of the bromide 9 c) , 588 mg of [1, 1-bis (diphenyl-
phosphino) ferrocene] Pd( II) Cl 2 and 183 mg of Cul are
stirred, at RT for 10 min, in 100 ml of THF, and solution
A is then added to this mixture. The resulting mixture is
stirred at RT for 19 h, and 20 0 ml of EA are then added;

2 0 the resulting mixture is washed 1 x with 2 00 ml of water
and 1 x with 200 ml of brine. The solvent is removed in
vacuo and the residue is chromatographed using EA/HEP
1:2.

2 g of a colorless oil are obtained.
25 R f (EA/HEP 1:2) = 0.25 MS (DCI) : 263 (M + H) +

e ) 4-1 sopropy 1 - 5 -methyl sul f ony 1 thiophene - 2 - carboguanidide
1 g of the methyl ester 9 d) is reacted with 1.1 g of
guanidine in analogy with Example 6 g) . 90 0 mg of an
amorphous powder are obtained.

30 R f (EA/MeOH 10:1) = 0.41 MS(ES) : 290 (M + H) +

The compound is converted into the methanesulf onate/
mp = 210°C

Example 10

3 -Methyl thiophene-2 -carboguanidide

2146707

- 40 -

nip (hydrochloride) : 232 °C MS (DCI) : 184 (M + H) +

Pharmacological data :

Inhibition of the Na + /H + exchanger of rabbit erythrocytes

New Zealand White rabbits (Ivanovas) were given a stan-
5 dard diet containing 2% cholesterol for six weeks in
order to activate Na + /H + exchange and thus to be able to
use flame photometry to determine the Na + influx into the
erythrocytes via Na + /H + exchange. The blood was removed
from the aural arteries and rendered incoagulable by the
10 addition of 25 IU of potassium heparin. One part of each
sample was used for the duplicate determination of the
hematocrit by centrif ugation . Aliquots of in each case
100 fil were employed for measuring the initial content of
Na + in the erythrocytes .

15 In order to determine the amiloride-sensitive sodium
influx, 100 fil of each blood sample were in each case
incubated, at pH 7.4 and 37 °C, in 5 ml of a hyperosmolar
salt/sucrose medium (mmol/1: 140 NaCl, 3 KC1, 150 su-
crose, 0.1 ouabain, 20 tris (hydroxymethyl) aminome thane ) .

20 The erythrocytes were then washed three times with ice
cold MgCl 2 /ouabain solution (mmol/1: 112 MgCl 2 , 0.1
ouabain) and hemolyzed in 2 . 0 ml of distilled water. The
intracellular content of sodium was determined by flame
photometry .

25 The nett influx of Na + was calculated from the difference
between the initial sodium values and the sodium content
of the erythrocytes following incubation. The amiloride-
inhibitable sodium influx was given by the difference in
the sodium content of the erythrocytes following incuba-

3 0 tion with and without 3 x 10 " 4 mol/1 amiloride. The same
procedure was also used in the case of the compounds
according to the invention.

2146707

- 41 -

Results

Inhibition of the Na + /H + -exchanger:

Example

IC 50 [/xmol/1]

1

0 .3

2

1. 0

-a

U.J

4

0.2

5

5 . 0

6

0.5

7

3

8

0.5

2146707

- 42 - HOE 94/F 094

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A heteroaroylguanidine of the formula I

R(3) R(2)

R(4) -^Sa^MD

in which:

HA is SO m , O, or NR(5),
5 m is zero, 1 or 2,

R(5) is hydrogen, (C^-Cg) -alkyl or -C^Hj^RlSl) f
am is zero, 1 or 2

R(81) is (C 3 -C 8 ) -cycloalkyl, or phenyl

which is not substituted or is substi-
10 tuted by 1-3 substituents from the group

F, Cl, CF 3 , methyl, methoxy or
NR(82)R(83), with R(82) and R(83) being H
or CH 3 ;

or

15 R(81) is (C x -C 9 ) -heteroaryl

which is linked via C or N and which is
unsubstituted or is substituted by 1-3
/ substituents from the group F, Cl, CF 3 ,
CH 3 , methoxy, hydroxyl, amino, methyl -
2 0 amino, or dime thy lamino;

one of the two substituents R(l) and R(2)

is -CO-N=C(NH 2 ) 2 ,
and whichever is the other is

hydrogen, F, Cl, Br, I, (C 1 -C 3 ) -alkyl, -OR(6),
25 C r F 2r+l' -CO-N=C(NH 2 ) 2 or -NR(6)R(7),

R(6) and R(7) are, independently, hydrogen or
(C 1 -C 3 ) -alkyl,
r is 1, 2, 3 or 4,
R(3) and R(4) are, independently of each other,
30 hydrogen, F, Cl, Br, I, -CsN, X- (CH 2 ) p - (C q -F 2q+1 ) ,

R(8)-SO bm , R(9)R(10)N-CO, R(ll)-CO- or R(12)R(13)N-

so 2 -,

where the perf luoroalkyl group is straight-chain

2146707

- 43 -

or branched,

X is oxygen, S or NR(14),

R(14) is H or (C^C^ -alkyl,
bm is zero, 1 or 2 ,

5 p is zero, 1 or 2 ,

q is zero, 1, 2, 3, 4, 5 or 6,

R(8), R(9), R(ll) and R(12) are, independently,
(c i- c 8> -alkyl, (C 3 -C 6 ) -alkenyl, -C n H 2n -
R(15) or CF 3 ,
10 n is zero, 1, 2, 3 or 4,

R(15) is (C 3 -C 7 ) -cycloalkyl, or phenyl
which is not substituted or is substi-
tuted by 1-3 substituents from the group
F, CI, CF 3 , methyl, methoxy or NR(16)R(17)
15 with R(16) and R(17) being H or C x -C 4 -

alkyl,

where R(9), R(ll) and R(12) also have the meaning
of H,

R(10) and R(13) are, independently,
20 H or (C a -C 4 ) -alkyl,

where R(9) and R(10) and also R(12) and R(13) can
together be 4 or 5 methylene groups, of which one
CH 2 group can be replaced by oxygen, S, NH, N-CH 3
or N-benzyl,

25 or

R(3) and R(4) are, independently of each other,
(C 1 -C 8 ) -alkyl or -C al H 2al R (18 ) ,
al is zero, 1 or 2 ,

R{18) is (C 3 -C B ) -cycloalkyl, or phenyl
30 which is not substituted or is substi-

tuted by 1-3 substituents from the group
F, CI, CF 3 , methyl, methoxy or
NR(19)R(20), with R(19) and R(20) being H
or CH 3 ;

35 or

R(3) and R(4) are, independently of each other,
(C-L-Cg) -heteroaryl,

which is linked via C or N and which is unsubsti-
tuted or is substituted by 1-3 substituents from

2146707

- 44 -

the group F, CI, CF 3 , CH 3 , methoxy, hydroxyl,
amino, methyl amino or dimethylamino;

or

R(3) and R(4) are, independently of each other,

0

-Y-^y-(C) h -(CHOH),-(CH s .) (CH0H) k -R(23)

<f V(C) fld -(CH0H) flf -(CH 2 ) af -(CH0H) afl -R(2O

<f V(C) oh -(CH0H) O0 -(CH 2 ) ap -(CH0H) flk -R(25)

0

11

5 Y is oxygen, -S- or -NR (22) - #

h, ad and ah are, independently, zero or 1,

i, j , k, ae, af, ag, ao, ap and ak are,
independently, zero, 1, 2, 3 or 4,

where, however, in each case,
10 h, i and k are not simultaneously zero,

ad, ae and ag are not simultaneously zero, and
ah, ao and ak are not simultaneously zero,

R(23), R(24), R(25) and R(22) are, independently,

hydrogen or (C^-Cg ) -alkyl.

15 or

R(3) and R(4) are, independently of each other,

hydrogen, F, Cl, Br, I, CN, (C 1 -C 8 ) -alkyl , (C^Cg) -
perf luoroalkyl, (C 3 -C 8 ) -alkenyl or 'C^l 2g R(2S) r
g is zero, 1, 2, 3 or 4,

20 R(26) is (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl

or naphthyl,

where the aromatic radicals are not sub-
stituted or are substituted by 1-3 sub-
stituents from the group F, Cl, CF 3 ,
25 methyl, methoxy or NR(27)R(28), with

2146707

- 45 -

R(27) and R(28) being H, (C^C^ -alkyl or
(C 1 -C 4 ) -perf luoroalkyl;

or

R(3) and R(4) are, independently of each other,
5 SR(29), -OR(30), -NR(31)R(32) or -CR (33 ) R (34) R (35) ;

R(29), R(30), R(31) and R(33) are, independently,
-C a H 2a - (C x -C 9 ) -heteroaryl

which is unsubstituted or is substituted
by 1-3 substituents from the group F, CI,
iO CF 3 , CH 3 , methoxy, hydroxyl, amino,

methylamino or dimethyl amino,
a is zero, 1 or 2,
R(32), R(34) and R(35) are, independently of each
other, defined as R(29), or are hydrogen, (C^
15 C 4 ) -alkyl or (C^-C^) -perf luoroalkyl ;

or

R(3) and R(4) are, independently of each other,

-R ( 98 }

— W w —

R(96), R(97) and R (98) are, independently, (C 1 -C 9 ) -
heteroaryl,

2 0 which is linked via C or N and which is

unsubstituted or is substituted by 1-3
substituents from the group F, CI, CF 3 ,
CH 3 , methoxy, hydroxyl, amino, methyl-
amino, dimethylamino or benzyl,
25 W is oxygen, S or NR(36)-,

R(36) is H or (C x -C 4 ) -alkyl,

or

R(3) and R{4) are, independently of each other,
R(37)-SO cm or R (3 8) R (39 ) N-S0 2 - ,

3 0 cm is 1 or 2,

R(37) is (C 1 -C 8 ) -alkyl, (C x -C 8 ) -perf luoroalkyl ,

(C 3 -C 8 ) -alkenyl or -C s H 2s -R (40) ,
s is zero, 1, 2, 3 or 4,

R(40) is (C 3 -C 8 ) -cycloalkyl, phenyl, biphenylyl

2146707

- 46 -
or naphthyl ,

where the aromatic radicals are not sub-
stituted or are substituted by 1-3 sub-
stituents from the group F, CI, CF 3 ,
5 methyl, methoxy or NR(41)R(42), with

R(41) and R(42) being H, (C^-C^) -alkyl or
(C 1 -C 4 ) -perf luoroalkyl ;
R(38) is H, (C^-Cg) -alkyl, (C^-Cg) -perf luoro-
alkyl, (C 3 -C 8 ) -alkenyl or -C^^-R (43 ) ,
10 w is zero, 1, 2, 3 or 4,

R(43) is (C 3 -C 8 ) -cycloalkyl, phenyl,
biphenylyl or naphthyl where
the aromatic radicals are not
substituted or are substituted by
15 1-3 substituents from the group F,

CI, CF 3 , methyl, methoxy or
NR(44)R(45), with R(44) and R(45)
being H, (C^-C^) -alkyl or (C x -C 4 ) -
perf luoroalkyl,

20 R(39) is H, (C^-C^) -alkyl or (C^-C^) -

perf luoroalkyl ,

where R(3 8) and R(39) can together be 4 or 5
methylene groups, of which one CH 2 group can be
replaced by oxygen, S, NH, N-CH 3 or N-benzyl ;

2 5 or

R(3) and R(4) are, independently of each other,
R(46)X{1)

X(l) is oxygen, S, NR(47), (D=0)A- or
NR(48)C=MN ( * 3 R(49)

3 0 M is oxygen or S,

A is oxygen or NR(50) ,

D is C or SO,

R(46) is (C 1 -C 8 ) -alkyl, (C 3 -C 8 ) -alkenyl,

(CH 2 ) b C d F 2d+1 or -C x H 2x -R(51) ,
35 b is zero or 1,

d is 1, 2, 3, 4, 5, 6 or 7,

x is zero, 1, 2, 3 or 4,

R(51) is (C 3 -C 8 ) -cycloalkyl , phenyl, bi-
phenylyl , naphthyl ,

2146707

- 47 -

10

15

or

20

where the aromatic radicals are not
substituted or are substituted by
1-3 substituents from the group F,
CI, CF 3 , methyl, methoxy or
NR(52)R(53); with R(52) and R(53)
being H, (C 1 -C 4 ) -alkyl or (C^-C^) -
perf luoroalkyl ;
R(47), R(48) and R(50) are, indepen-
dently, hydrogen, ( c i" C 4 ) -alkyl or
^ c i" C 4^ -perf luoroalkyl,
R(49) is defined as R{46), where
R(46) and R(47) and, respectively, R(46) and R(48)
can together be 4 or 5 methylene groups, of which
one CH 2 group can be replaced by oxygen, S, NH,
N-CH 3 or N-benzyl,

where A and N^** are bonded to the phenyl nucleus
of the benzoylguanidine parent substance;

R(3) and R(4) are, independently of each other,

-SR(64), -OR(65), -NHR(66), -NR (67) R (68) ,

-CHR(69)R(70) ,

-C

R(54)

R ( 55 )
OH

R( 58 )

-C-C R ( 5 6 ) , -C C-R ( 57 ) f

R( 59 )

-C

R(60)

0

II
C

R(6I )

R ( 62 )_

¥ -R(63)

R(64), R(65), R(66), R(67) and R(69) are, identi-
cally or differently,

- (CH 2 ) y - (CHOH) z - (CH 2 ) aa - (CH 2 OH) t -R(71) or
25 - (CH 2 ) ab -0- (CH 2 -CH 2 0) ac -R(72) ,

R(71) and R(72) are hydrogen or methyl,
u is 1, 2, 3 or 4,
v is zero, 1, 2, 3 or 4,

y, z and aa are, identically or differently,
30 zero, 1, 2, 3 or 4,

2146707

- 48 -

t is 1, 2, 3 or 4,
R(68), (R70), R(54) and R(55) are, identically or
differently,

hydrogen or (C^-Cg) -alkyl, or
5 R(69) and R(70) and, respectively, R(54) and R(55)

are, together with the carbon atom carrying them, a
(C 3 -C g ) -cycloalkyl;
R(63) is

H, (C^-Cg) -alkyl, (C 3 -C 8 ) -cycloalkyl or

10 -C e H 2e -R(73) ,

e is zero, 1, 2, 3 or 4,
R(56), R(57) and R(73) are, independently,
phenyl ,

which is unsubstituted or is substituted by 1-3
15 substituents from the group F, CI, CF 3 , methyl,

methoxy or NR(74)R(75) with R(74) and R(75)

being H or (C^-C^) -alkyl,
or R(56), R(57) and R{73) are, independently, (C^-
C g ) -heteroaryl,

20 which is unsubstituted or is substituted as

phenyl ;

R(58), R(59), R(60), R(61) and R(62) are hydrogen or
methyl,

or

25 R(3) and R(4) are, independently of each other, R(76)-NH-

so 2 -,

R(76) is R(77)R(78)N- (C=Y' )

Y' is oxygen, S or N-R(79),
R(77) and R(78) are, identically or
30 differently,

H, (Ci-Cg) -alkyl, (C 3 -C 6 ) -alkenyl ,
or -C f H 2f -R (80) ,
f is zero, 1, 2, 3 or 4,
R(80) is (C 5 -C 7 ) -cycloalkyl, or
3 5 phenyl

which is unsubstituted or is sub-
stituted by 1-3 subs tituents from
the group F, CI, CF 3 , methoxy or
(C 1 -C 4 ) -alkyl, or

2146707

- 49 -

R(77) and R(78) together form 4 or 5 methylene
groups, of which one CH 2 group can be replaced by
oxygen, S, NH, N-CH 3 or N-benzyl, where
R(79) is defined as R(77) or is amidine;

or

R(3) and R(4) are, independently of each other,
NR(84)R(85) ,

R(84) and R(85) are, independently of each
other,

H or (C^-C^) -alkyl, or, together, can be 4 or 5
methylene groups, of which one CH 2 group can be
replaced by oxygen, S, NH, N-CH 3 or N-benzyl,
or of which one or two CH 2 groups can be
replaced by CH-C^H^^,
and the pharmaceutically tolerated salts thereof,

where, however, compounds are excepted in which the
radicals R(l) to R(4) and also HA are combined in the
following manner:

R(D

R(2)

R(3)

R(4)

HA

CON=C(NH 2 )

H

H

Et

0

CON=C (NH 2 )

H

H

Me

O

CON=C (NH 2 )

H

H

H

0

2. A heteroaroylguanidine I as claimed in claim 1,

wherein :

HA is SO m , O or NR(5) ,

m is zero, 1 or 2,

R(5) is hydrogen or methyl,
one of the two substituents R(l) and R(2) is

-CO-N«C(NH 2 ) 2 ,

and whichever is the other is hydrogen, F, CI, CH 3 , -OH
or -CO-N=C(NH 2 ) 2 ,

R(3) is hydrogen, F, Cl, Br, I, -CsN, C q -F 2g+1 ,
R(8) -S0 2 ,

R(9)R(10)N-CO, R(ll)-CO- or R ( 12 ) R (13 ) N- S0 2 - #

2146707

- 50 -

where the perf luoroalkyl group is straight-chain
or branched,

q is zero, 1, 2, 3, 4, 5 or 6,

R(8) # R(9), R(ll) and R(12) are, independently,
5 (C 1 -C 8 ) -alkyl, (C 3 -C 4 ) -alkenyl, -C n H 2n -R(15) or

CF 3 ,

n is zero, 1, 2, 3 or 4,

R(15) is (C 3 -C g ) -cycloalkyl, or phenyl

which is not substituted or is substi-
10 tuted by 1 - 2 substituents from the

group F, CI, CF 3 , methyl, methoxy or

NR(16)R(17), with R(16) and R(17) being

H or methyl,

where R(9), R(ll) and R(12) also have the meaning
15 of H,

R(10) and R(13) are, independently, H or
methyl,

or

R(3) is (C 1 -C 8 ) -alkyl or -C al H 2al R (18 ) ,
20 al is zero, 1 or 2,

R(18) is (C 3 -C 6 ) -cycloalkyl, or phenyl

which is not substituted or is substi-
tuted by 1 - 2 substituents from the
group F, CI, CF 3 f methyl, methoxy or
25 NR(19)R(20), with R(19) and R(20) being H

or CH 3 ;

or

R(3) is quinolyl, isoquinolyl, pyrrolyl, pyridyl or

imadazolyl which are linked via C or N and
3 0 which are unsubsti tuted or are substituted by

1-2 substituents from the group F, CI, CF 3 ,
CH 3 , methoxy, hydroxyl, amino, methylamino or
dime thy lamino ;

or

35 R (3) is -CssCR (56) ,

R(56) is phenyl,

which is unsubsti tuted or is substituted by 1 -
2 substituents from the group F, CI, CF 3 ,
methyl, methoxy or NR(16)R(17), with R{16) and

2146707

- 51 -

R(17) being H or CH 3 f

R(4) is

0

-Y-V7-(C) h -(CH0H),-(CH 2 ) r (CHOH) k -R(23 )

(CHOH) 0 ,-(CH 2 ) of -(CHOH) og -R(24)

(CHOH) BO -(CH 2 ) op -(CHOH) ok -R(25)

Y is oxygen, -S- or -NR (22 ) - ,
h, ad and ah are, independently, zero or 1,
5 i, k, ag, ao and ak are, independently, zero, 1, 2

or 3 ,

j, af and ap are, independently, zero or 1,
where, however, in each case,

h, i and k are not simultaneously zero,
10 ad, ae and ag are not simultaneously zero, and

ah, ao and ak are not simultaneously zero,
R(23), R(24), R(25) and R(22) are, independently,
hydrogen or methyl,

or

15 R(4) is hydrogen, F, CI, Br, CN, (C 1 -C 8 ) -alkyl, C q -F 2q+1 ,

(C 3 -C 8 ) -alkenyl or -C g H 2g R(26) ,

where the perf luoroalkyl group is straight -chain
or branched,

g is zero, 1, 2, 3 or 4,
20 g is zero, 1 or 2,

R(26) is (C 3 -C 8 ) -cycloalkyl, or phenyl

which is not substituted or is substituted by
1-2 substituents from the group F, CI, CF 3 ,
methyl, methoxy or NR(27)R(28), with R(27) and
25 R(28) being H or CH 3 ,

2146707

- 52 -

or

R(4) is SR(29), -OR(30), -NR(31)R(32) or

-CR(33)R(34)R(35) ;

R(29), R(30), R(31) and R(33) are, independently,
5 -C a H 2a - (C^Cg) -heteroaryl, selected from the group

consisting of pyrrolyl, imidazolyl, pyrazolyl and
pyridyl,

which is unsubstituted or is substituted

by 1-2 substituents from the group F,
10 CI, CF 3 , CH 3 , methoxy, hydroxyl, amino,

methylamino or dimethyl amino,

a is zero or 1,
R(32), R(34) and R(35) are, independently of each
other,

15 hydrogen or CH 3 ,

or

R(4) is

— W w —

20

25

30

or
R(4)

R(96), R(97) and R(98) are, independently, pyrrolyl,
imidazolyl, pyrazolyl or pyridyl,

is unsubstituted or is
radicals from the group

CH, , methoxy, dimethyl -

which, in each case,
substituted by 1-2
comprising F, CI, CF 3
amino or benzyl,
W is oxygen, S or NR(36)-,

R(36) is H or methyl,

is R(37)-SO cm or R (3 8) R (39) N-S0 2 - ,

R(37) is (C^Cg) -alkyl, CF 3 , (C 3 -C 4 ) -alkenyl or -

C s H 2s- R ( 40 > '

s is zero or 1,

R(40) is (C 3 -C 6 ) -cycloalkyl, or phenyl

which is not substituted or is substi-
tuted by 1-2 substituents from the
group F, CI, CF 3 , methyl, methoxy or

2146707

- 53 -

NR(41)R(42), with R(41) and R(42) being H
or CH 3/

R(38) is H, (C-l-C^j) -alkyl, CF 3 , (C 3 -C 4 ) -alkenyl

or -C w H 2w -R(43) ,
5 w is zero or 1

R(43) is (C 3 -C 8 ) -cycloalkyl, or phenyl

which is not substituted or is sub-
stituted by 1-2 substituents from
the group F, CI, CF 3 , methyl,
10 methoxy or NR(44)R(45), with R(44)

and R(45) being H, (C^-C^) -alkyl or
CH 3 ,

R(39) is H or CH 3 ,

where R(38) and R(39) can together be 4 or 5
15 methylene groups, of which one CH 2 group can be

replaced by oxygen, S, NH, N-CH 3 or N-benzyl;

or

R(4) is R(46)X(1)

X(l) is oxygen, S, NR(47), (C=0)A- or

2 0 NR(48) C=MN ( * } R(49)

M is oxygen,
A is oxygen or NR(50),
R(46) is (C 1 -C 6 ) -alkyl, (C 3 -C 4 ) -alkenyl,

(CH 2 ) b C d F 2d+1 or -C x H 2x -R(51),
25 b is zero or 1,

d is 1, 2, 3, 4, 5, 6 or 7,
x is zero or 1,

R(51) is (C 3 -C 8 ) -cycloalkyl, or phenyl

which is not substituted or is sub-

3 0 stituted by 1-2 substituents from

the group F, CI, CF 3 , methyl,
methoxy or NR(52)R(53); with R(52>
and R(53) being H or CH 3 ,
R(47) , R(48) and R(50)
3 5 are hydrogen or (C^-C^ -alkyl,

R(49) is defined as R(46), where
R{46) and R(47) and, respectively, R(46) and
R(48) can together be 4 or 5 methylene groups,
of which one CH 2 group can be replaced by

2146707

- 54 -

oxygen, S, NH, N-CH 3 or N-benzyl,

where A and N*** are bonded to the phenyl

nucleus of the benzoylguanidine parent

substance;

5 or

R(4) is -SR(64), -OR(65), -NHR(66), -NR (67 ) R ( 68 ) ,
-CHR(69)R(70) ,

^R(54)

-C R(55)

^OH

R ( 58 )

-CECR(56) t -C C-R(57) .

R ( 5 9 )

-C

I

R ( SO )

0

tl

•c

R(61 )
C

R(62)_

¥ -R(63)

R(64), R(65), R(66), R(67) and R(69) are,
identically or differently,
10 - (CH 2 ) y - (CHOH) z - (CH 2 ) aa - (CH 2 OH) t -R(71) or

- (CH 2 ) ab -0- (CH 2 -CH 2 0) ac -R(72) ,

R(71) and R(72) are hydrogen or methyl,
u is 1 or 2,
v is zero, 1 or 2,
15 y, z and aa are, identically or differently,

zero, 1 or 2,
t is 1, 2 or 3,
R(68), R(70), R(54) and R(55) are, identically or
differently,

2 0 hydrogen or CH 3 ,

or

R(69) and R(70) and, respectively, R(54) and R(55)
are, together with the carbon atom carrying them, a
(C 3 -C 6 ) -cycloalkyl;
25 R(63) is

H, (C 1 -C 4 ) -alkyl, (C 3 -C e ) -cycloalkyl or

-C e H 2e -R<73) ,

e is zero, 1 or 2,
R(56), R(57) and R(73) are, independently,

3 0 phenyl

2146707

- 55 -

which is unsubstituted or is substituted
by 1-2 substituents from the group F,
CI, CF 3 , methyl, methoxy or NR(74)R(75),
with R(74) and R(75) being H or CH 3 ,

5 or

R(56), R(57) and R(73) are, independently,

(C 1 -C 9 ) -heteroaryl, selected from the group con-
sisting of pyrrolyl, imidazolyl, pyrazolyl and
pyridyl,

10 which is unsubstituted or is substituted

as phenyl ;
R(58), R(59), R<60), R(61) and R(62)
are hydrogen or methyl,

or

15 R(4) is R(76) -NH-S0 2 -,

R(76) is R(77)R(78)N- (C=Y' )
Y' is oxygen, S or N-R(79),

R(77) and R(78) are, identically or
differently,

20 H, (C 1 -C 4 ) -alkyl, (C 3 -C 4 ) -alkenyl or

-C f H 2f -R(80) ,
f is zero or 1,
R(80) is

(C 5 -C 7 ) -cycloalkyl , or phenyl
25 which is unsubstituted or is

substituted by 1-2 substi-
tuents from the group F, CI,
CF 3 , methoxy or CH 3 , or
R(77) and R(78) together form 4 or 5
3 0 methylene groups, of which one CH 2 group

can be replaced by oxygen, S, NH, N-CH 3 or
N-benzyl, where
R<79) is defined as R(77),

or

35 R(4) is NR(84)R{85) ,

R(84) and R(85) are, independently of each other,
H or (C 1 -C 4 ) -alkyl, or together form 4 or 5
methylene groups, of which one CH 2 group can be
replaced by oxygen, S, NH, N-CH 3 or N-benzyl,

2146707

- 56 -

or of which one or two CH 2 groups can be
replaced by CH-CH 3 .
3. A heteroaroylgnanidine I as claimed in claim 1,

wherein:
5 R(l) is

-CO-N=C (NH 2 ) 2

HA is

S, O, NH or NCH 3 ,
and the radicals R(2) to R(4) are combined as follows:

2146707

- 57 -

R(2)

R(3) | R(4)

U

n

n-BuNH-

Cl

H

H 2 NS0 2 -

H

MeS0 2

H

o-

Me

H

o-

©-

H

/ — v

o-

Me

H

O

CI

H

Vj

MeSO r

H

MeS0 2

NH 2

H

MeS0 2 -

H

MeS0 2 -

2146707

- 58 -

H

MeS0 2 -

C 1

H

MeS0 2 -

ii . ^ / ( A\ hi ii

M « 0 Jf— N H —

H

MeS0 2 -

rl

H

Cl-

o-

H

MeS0 2 .

(CH 3 ) 2 -CHCH 2 -0-

H

MeS0 2 .

H

MeS0 2 .

M e

H

MeSO

M e

ISC

H

Q

C I

2146707

- 59 -

H

C I

C I

H

CH

H

C I

H

OM e

H

H

MeS0 2 -

C I

C I

H

MeS0 2 -

C I

C I

Me

Me

H

H

MeS0 2 -

i-Pr

H

CF.

H

H

H

TT

MeS0 2 -
MeSOo-

Cl

MeNH-
Et 2 N-

2146707

- 60 -

1 H

t-Bu

OH

H

MeS0 2 -

o

H

MeS0 2 -

H

MeS0 2 -

a,.

H

MeS0 2 -

C 1

H

MeS0 2 -

o-

1 ii

H

MeS0 2 -

2-Napntnyi

H

MeS0 2 -

H

W

Me

H

M •

(Qr-

H

CI

Et 2 N-

H

Me 2 N-

H

H

MeSO z -

■

2146707

- 61 -

H

Br

NH 2

H

CI

H

H

MeS0 2 -

H

MeS0 2 -

C 1

H

CF 3

CF 3

H

Me

Me

Ul

1
1

M

IV) e

H

n

LI

it

n

t-Bu

Ul

ivieoU2

H

Me

CI

H

Br

Me

H

CI

MeO-

H

MeCO-

Cr

H

Br

Br

H

MeS0 2 -

^^^^

^^^C H 2 - C H 2 -

H

MeS0 2 -

NH 2

Br

Me

H

Me 2 N-

t-Bu

H

MeS0 2 -

H

\ — /

H

2146707

f it

o-

M6U-

H

Me

Br

H

CI

F

H

t-Bu

Li
H

NH 2

CI

H

o-

Me 2 N

H

Me 2 N

CI

H

MeS0 2 -

7-lsoquinolinoxy

H

MeS0 2 -

6-quinolinoxy

H

1

MeS0 2 -

H

MeS0 2 *

H

MeSOo-

(CH'il'iCn'Cnn" II

H

MeS0 2 -

H

<0>-°- |

H

H

1 1 1

Me

ifi w

Me 2 N-

H

H

Me

H

CI

l-Pr

- 63 -

2146707

H

\=J

i-Pr |

H

MeS0 2 -

5-quinolinoxy

H

Cr

CF 3

H

i-Pr

MeS0 2 -

H

i-Pr

H

H

i-Pr

NH 2

Br

Br

H

MeSO-,-

OH

H

MeSD 2 -

H

MeS0 2 -

Bn

H

1 1

Cl

_ 0

u
n

i-Pr

H

MeHN-

i-Pr

H

Cl

CI

H

CI

H 2 N-

H

CI

H 2 N

H

MeS0 2 -

H

- 64 -

2146707

H

MeS0 2 -

<
<

M e

H

"cT.

~TT

~H

"TT
"FT
TT

Me 2 N-

H

Br
Me
Me 2 N

Ch,c6-

i-Pr
Me

cl

Me
MeHN-
(CH 3 ) 2 CH-CH

H

MeS0 2 -

H

CF r O-

H

H

Me

Me 2 N

H

CI

Me 2 N-

H

MeS0 2 -

NU t

H

CH3CO-

i-Pr

H

Br

BnO-

H

CF.

Br

H

i-Pr

MeO-

H

MeS0 2 -

0-

H

MeS0 2 -

H

"TT

CF.

MeO-
~Br~"
H

t-Bu

TpT
"TT

H

CF

2146707

- 65 -

H

Ph

CF 3
1-lmidazolyl

H

MeCO-

t-Butylmethyl

H

Br

H

H

Br

CF.

MeO-

PhO-

H

CF.

Cyclopentyl

H

MeS0 2 -

Cyclobutyl

H

Me

CF-

H

MeSOo-

H

Oh

t-Butyl

H

CI

OMe

H

CF 3

i-Pr

F

I CF3 I

H

F

H

CF 3 J

H

t-Butyl

OMe

H

MeCO-

XX'

H

t-Butyl

i-Butyl

H

CF 3 CF 2 -

i-Propyl

H

CI

CF 3 -S0 2 -

CF.

H

2146707

66 -

CI

H

CF.

H

H

Perfluoro-i-propyl

H

H

H

H

MeSO

\

0-

H

H

Perfluoro-n-propyl

H

CF.

C-

H

CF.

C I

0-

H

CF.

H

CF

H

MeSOo-

H

t- Butyl

i-Propyl

H

t- Butyl

n-Butyl

H

i-Propyl

H

i-Butyl

H

H
TT

CI

TT
TT
TT

1-lmidazolyl
CF 3 -CF 2 -

CF.

2116707

- 67 -

H

MeS0 2

>~cr

H

CF 3 S0 2

i-Propyl

4. A process for preparing a compound I as claimed

in claim 1, wherein

a compound of the formula II

0

in which L is a leaving group which can readily be
5 substituted nucleophilically , is reacted with guanidine.

5, The use of a compound I as claimed in claim 1 for
preparing a medicament for the treatment of arrhythmias.

6. A method for treating arrhythmias, wherein an
effective quantity of a compound I as claimed in claim 1

10 is treated with the customary additives and administered
in a suitable form for administration.

7 . The use of a compound I as claimed in claim 1 for

preparing a medicament for the treatment or prophylaxis
of cardiac infarction.
15 8. The use of a compound I as claimed in claim 1 for

preparing a medicament for the treatment or prophylaxis
of angina pectoris.

9. The use of a compound I as claimed in claim 1 for
preparing a medicament for the treatment or prophylaxis

2 0 of ischemic conditions of the heart.

10. The use of a compound I as claimed in claim 1 for
preparing a medicament for the treatment or prophylaxis
of ischemic conditions of the peripheral and central
nervous system and of stroke.

25 11. The use of a compound I as claimed in claim 1 for

2146707

- 68 -

preparing a medicament for the treatment or prophylaxis
of ischemic conditions of peripheral organs and limbs.

12 . The use of a compound I as claimed in claim 1 for
preparing a medicament for the treatment of shock

5 conditions,

13 . The use of a compound I as claimed in claim 1 for
preparing a medicament for employment in surgical
operations and organ transplantations .

14. The use of a compound I as claimed in claim 1 for
10 preparing a medicament for the preservation and storage

of transplants for surgical procedures.

15. The use of a compound I as claimed in claim 1 for
preparing a medicament for the treatment of diseases in
which cell proliferation represents a primary or

15 secondary cause, and consequently its use as an anti-
atherosclerotic agent, or as an agent against diabetic
late complications, cancerous diseases, fibrotic diseases
such as pulmonary fibrosis, hepatic fibrosis or renal
fibrosis, and against hyperplasia of the prostate.

20 16. The use of a compound I as claimed in claim 1 for

preparing a scientific tool for inhibiting the Na + /H" 1 "
exchanger and for diagnosing hypertension and
proliferative diseases .

17. A medicine containing an effective quantity of a

25 compound I as claimed in claim 1.